Initial work on this protein was designed to utilize fluorinated analogs of the cyclic urea inhibitors of HIV-protease originally pioneered by DuPont-Merck and more recently evaluated by Abbott Labs. It was decided, however, that it would be useful to obtain a more basic understanding of the nature of the active site and, since the protease is in relatively short supply, most of the work over the past year has focused on the aspartyl protease, pepsin. In addition to being a member of the aspartyl protease family, there is significant homology between the active sites of the pepsin and HIV protease, as is apparent from the observation that pepsin inhibitors such as acetyl pepstatin are also fairly good inhibitors of the protease. Previously studied inhibitors of pepsin include peptides containing the statine residue ([3S,4S]-4-amino-3- hydroxy-6-methylhepatnoic acid), peptide aldehydes such as N-Ac-Leu-Val- Phenylalaninal, and aliphatic alcoholes. NMR studies of the interaction of these inhibitors with pepsin are in progress. A combination of NMR and activity studies has suggested a new class of inhibitors for this type of enzyme, which are currently under evaluation. Pharmacological modification of viral proteins, particularly the viral coat protein, represents a useful approach to eliciting antibodies against the modified protein. Aspirin is the most common pharmacological acetylating agent, with widely varying specificity. We have recently proposed using aspirin to modify the viral coat protein in order to study the specificity and kinetics of this modification. Initial work will utilize peptides derived from gp120.